Opiates are important for the treatment of pain, but their abuse presents a major health proglem. Understanding opioid actions is crucial to their rational use clinically and the development of potential treatments for abuse. Opiates and the opioid peptides act through a family of receptors, of which a number have been cloned. Studies on the actions of these receptors carried out in tissue culture have provided important information regarding their biochemistry. However, these advances now need to be taken into behavioral systems. Recent work using antisense approaches has confirmed the importance of the cloned opioid receptors in opioid pharmacology. Antisense techniques can be used to selectively target individual exons, permitting the examination of splice variants. Using this antisense mapping approach against the MOR-1 clone, which encodes a mu receptor, we found different selectivity profiles for morphine and its extremely potent metabolite morphine-6beta-glucuronide (M6G), implying that they act through distinct receptors. This has now been confirmed in MOR-1 knockout mice. These animals are insensitive to morphine, but retain their sensitivity to M6G. The importance of this M6G receptor is enhanced by the additional observations that heroin and several highly potent clinical analgesics also act through the M6G receptor. Despite the inactivity of morphine in the knockout mice, heroin retains its full analgesic activity. Thus, the M6G receptor might be considered a new heroin receptor. This concept provides important insights into future studies of the mu opioid system. Another member of the opioid receptor family has also proven very interesting. The orphan opioid receptor has led to the identification of a new series of peptides termed orphanin FQ or nociceptin. These agents have a complex pharmacology which will be explored in further detail. Finally, prior work has established that the sigma receptor activates a potent anti-opioid system within the central nervous system. This system is responsible for variations in analgesic sensitivity among some species. We recently cloned the murine sigma receptor and plan to utilize it to gain a better understanding at the molecular level of this system through antisense and other approaches.